Our long-range goal is to improve the therapy of Myeloma. The central hypothesis for the proposed research is that inhibition of specific gene targets will modulate the sensitivity of Myeloma cells to bortezomib and other proteasome inhibitors. Our objective in this proposal is to apply advanced functional genomic strategies to identify and rapidly validate the critical role of candidate genes in drug performance and advance this information clinically.
Specific Aim 1 will address the influence of recently-identified promiscuous mutations of NFKappaB in Myeloma and their relationship to proteasome inhibitor sensitivity.
Aim 2 will utilize an innovative high-throughput siRNA screen to identify critical genes or pathways which sensitize or protect Myeloma cells from bortezomib- or PR-171-induced cell death. A library of 10,000 siRNA targeting the druggable genome will be applied.
Specific Aim 3 is structured to enable rapid validation of the hypothesis that the candidate genes prioritized in Specific Aim 2 are functionally relevant as sensitizing targets in Myeloma cells.
In Specific Aim 4, we will use tissues and genetic data from clinical trials and clinical databases to rapidly validate the clinical importance of prioritized candidates, and previously-described targets of bortezomib. The ultimate goal of our entire study will be to generate new sensitizer drugs to be used in combination therapy to increase the clinical success rate of bortezomib or other PI therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129009-03
Application #
7626793
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Song, Min-Kyung H
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$304,166
Indirect Cost
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259